Purpose: To review information on the use of laboratory tests in screening, diagnosis, and monitoring of acute and chronic hepatic injury.

Data Sources and Study Selection: A MEDLINE search was performed for key words related to hepatic diseases, including acute hepatitis, chronic hepatitis, alcoholic hepatitis, cirrhosis, hepatocellular carcinoma, and etiologic causes. Abstracts were reviewed, and articles discussing use of laboratory tests selected for review. Additional articles were selected from the references.

Guideline Preparation and Review: Drafts of the guidelines were posted on the Internet, presented at the AACC Annual Meeting in 1999, and reviewed by experts. Areas requiring further amplification or literature review were identified for further analysis. Specific recommendations were made based on analysis of published data and evaluated for strength of evidence and clinical impact.

Recommendations: Although many specific recommendations are made in the guidelines, only some summary recommendations are listed here. In acute hepatic injury, prothrombin time and, to a lesser extent, total bilirubin are the best indicators of severity of disease. Although ALT is useful for detecting acute and chronic hepatic injury, it is not related to severity of acute hepatic injury and only weakly related to severity of chronic hepatic injury. Specific tests of viral markers should be the initial differential tests in both acute and chronic hepatic injury; when positive, they are also useful for monitoring recovery from hepatitis B and C.

Diagnosis and Monitoring of Hepatic Injury. II. Recommendations for Use of Laboratory Tests in Screening, Diagnosis, and Monitoring

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.1840190111

Prospective study of α-fetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma

Lectin-affinity electrophoretic separation of serum alpha-fetoprotein (AFP) was carried out using AFP Differentiation Kits, which used Lens culinaris agglutinin-A (Kit L) and erythroagglutinating phytohemagglutinin (Kit P). Separated AFP bands were detected with a sensitive antibody-affinity blotting technique and determined quantitatively by densitometry, and the results were expressed as percentages of the intensity of total AFP bands. Sera from 424 patients with acute hepatitis, chronic hepatitis, liver cirrhosis, hepatocellular carcinoma, and extrahepatic tumors were assayed for proportion of AFP present as Lens culinaris agglutinin-A-reactive AFP (AFP-L3) and erythroagglutinating phytohemagglutinin-reactive AFPs (AFP-P4+P5). From the maximum Youden indices determined, cutoff levels were set at 15% for both AFP-L3 and AFP-P4+P5 to discriminate between patients with chronic hepatitis and liver cirrhosis and patients with hepatocellular carcinoma. AFP-L3 and AFP-P4+P5 showed sensitivities of 55.3 and 61.0% at specificities of 93.9% and 82.3%, respectively. Thirty-eight % of tumors that measured less than 20 mm in diameter were positive for AFP-L3 and AFP-P4+P5. AFP-L3 exceeded the cutoff level of 15% 4.0 +/- 4.9 months before detection of hepatocellular carcinomas by imaging techniques with a sensitivity of 48% and a specificity of 81%. Thus, these tests are useful for the early detection of hepatocellular carcinomas in patients with hepatitis or liver cirrhosis.

https://cancerres.aacrjournals.org/content/canres/53/22/5419.full.pdf

A Collaborative Study for the Evaluation of Lectin-Reactive α-Fetoproteins in Early Detection of Hepatocellular Carcinoma

There has been limited analysis of the effects of hepatocellular carcinoma (HCC) on liver metabolism and circulating endogenous metabolites. Here, we report the findings of a plasma metabolomic investigation of HCC patients by ultraperformance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS), random forests machine learning algorithm, and multivariate data analysis. Control subjects included healthy individuals as well as patients with liver cirrhosis or acute myeloid leukemia. We found that HCC was associated with increased plasma levels of glycodeoxycholate, deoxycholate 3-sulfate, and bilirubin. Accurate mass measurement also indicated upregulation of biliverdin and the fetal bile acids 7α-hydroxy-3-oxochol-4-en-24-oic acid and 3-oxochol-4,6-dien-24-oic acid in HCC patients. A quantitative lipid profiling of patient plasma was also conducted by ultraperformance liquid chromatography-electrospray ionization-triple quadrupole mass spectrometry (UPLC-ESI-TQMS). By this method, we found that HCC was also associated with reduced levels of lysophosphocholines and in 4 of 20 patients with increased levels of lysophosphatidic acid [LPA(16:0)], where it correlated with plasma α-fetoprotein levels. Interestingly, when fatty acids were quantitatively profiled by gas chromatography-mass spectrometry (GC-MS), we found that lignoceric acid (24:0) and nervonic acid (24:1) were virtually absent from HCC plasma. Overall, this investigation illustrates the power of the new discovery technologies represented in the UPLC-ESI-QTOFMS platform combined with the targeted, quantitative platforms of UPLC-ESI-TQMS and GC-MS for conducting metabolomic investigations that can engender new insights into cancer pathobiology.

https://cancerres.aacrjournals.org/content/canres/71/21/6590.full.pdf

Aberrant lipid metabolism in hepatocellular carcinoma revealed by plasma metabolomics and lipid profiling.

PURPOSE: To review characteristic findings of fibrolamellar hepatocellular carcinoma (HCC) at computed tomography (CT) and magnetic resonance (MR) imaging. MATERIALS AND METHODS: The authors retrospectively reviewed the clinical, pathologic, and preoperative imaging findings in 31 patients with histologically proved fibrolamellar HCC. Dynamic contrast material–enhanced CT of the liver was performed in 31 patients, helical multiphase CT in 21, and MR imaging in 11. Complete resection was performed in 17 patients, and imaging-pathologic correlation was performed. RESULTS: Large tumors (mean diameter, 13 cm) were depicted at CT and MR in all cases. At CT, the margins of the tumors were well defined in 24 (77%) of 31 cases, calcifications were depicted in 21 (68%), a central scar in 22 (71%), and abdominal lymphadenopathy in 20 (65%). In 20 (80%) of 25 cases with hepatic arterial phase CT images, all tumors were heterogeneous and depicted areas of hypervascularity. At MR imaging, tumors were hypointense to li...

Fibrolamellar Hepatocellular Carcinoma: Imaging and Pathologic Findings in 31 Recent Cases

Des-gamma-carboxy prothrombin [DCP], a protein induced by vitamin K absence or antagonist-II and also abbreviated PIVKA-II, was evaluated as a serologic marker for hepatocellular carcinoma (HCC). Its plasma levels were measured by enzyme immunoassay (E-1023) using an anti-DCP monoclonal antibody in 514 patients with various diseases. Of 120 patients with HCC, 76 (63%) had abnormal DCP levels greater than 0.1 arbitrary unit (AU)/ml and 58 (48%) showed levels greater than 0.3 AU/ml. When a diagnostic minimum level of 0.3 AU/ml was applied for DCP, false-positive cases of HCC were virtually eliminated. In some patients with HCC, plasma DCP levels normalized after surgical resection of the tumor. However, they rose again later with recurrence of the disease. The sensitivity of DCP in the diagnosis and monitoring of HCC was increased by serial and simultaneous determinations of alpha-fetoprotein (AFP), because high DCP levels were observed more often in low AFP-producing HCC patients. Elevated plasma DCP levels were not related to low vitamin K concentration in the serum. In fact, in many patients vitamin K administration resulted in only a moderate reduction of DCP levels. These results suggested strongly that DCP was synthesized by the hepatoma cells.

Plasma abnormal prothrombin (Des-γ-carboxy prothrombin) as a marker of hepatocellular carcinoma

In order to study the clinical significance of cholylglycine (CG), CG in both fasting levels and after oral loading of 300 mg ursodeoxycholic acid (UDCA) were determined by radioimmunoassay in 313 patients with various liver diseases. Elevated fasting CG levels were found in 66.6% of patients with acute hepatitis (AH), 34.8% chronic inactive hepatitis (CIH), 79.3% chronic active hepatitis (CAH), 97.1% liver cirrhosis (LC), 94.7% hepatocellular carcinoma (HCC), and 80% of gall stones (GS). Changes of fasting CG during the course of AH were found to be parallel with values of transaminases. On oral loading of UDCA, different CG responses were found in CIH and CAH, and in compensated and decompensated LC. From these results we concluded that the determinations of serum CG gave additional informations of various liver diseases.

Clinical usefulness of serum cholylglycine determination in various liver diseases.

ルポイド肝炎の診断後,7年余を経て肝細胞癌を併発した1例を報告した.症例は60歳の主婦で,1976年,偶然の機会に肝機能障害を指摘され,1978年,四肢関節痛,上下肢浮腫,黄疸ならびに腹水を来たし,当科に入院した.当時,γ-globulin (γ-glb) 5.0g/dl, IgG 6,350 mg/dl, LE cell,抗核抗体および抗DNA抗体が陽性で,ルポイド肝炎と診断された.約2年間,ステロイドを投与され,症状は軽快し,1979年10月の腹腔鏡検査では,肉眼的に結節肝,組織学的に慢性活動性肝炎であった.1985年10月,AFP高値および各種画像診断により,肝細胞癌の合併が明らかとなったが,1986年3月,腹腔内大量出血により死亡した.かかる症例は極めて稀と思われ報告する.

https://www.jstage.jst.go.jp/article/kanzo1960/28/6/28_6_772/_pdf

A case of lupoid hepatitis associated with hepatocellular carcinoma.

市販鎮痛剤の乱用によると考えられる劇症肝炎の39歳女性の1救命例を報告した.20歳頃より生理痛・頭痛のため,ブロム剤を20錠/日服用していた.36歳時,突然頭痛,全身痙攣を来たし,近医にて頭部CT上脳萎縮を指摘された.以後,セデスAを多い時で40錠/日服用するようになった.1週間来の全身倦怠感,頭痛,下痢に気付き,肝障害・prothrombin時間の延長あり,劇症肝炎を疑われ昭和60年8月18日当院に入院した.血漿交換,glucagon・insulin療法により救命し,第26病日の腹腔鏡下肝生検では急性肝炎再生像であった.しかし,第12病日よりJackson型の痙攣が出現し,第80病日の頭部CTで前頭葉の萎縮を認めた.劇症肝炎の成因として,IgM-HBc抗体およびIgM-HA抗体は共に陰性であることより,乱用していた鎮痛薬に含まれるacetaminophenの関与が推測された.脳萎縮はすでに3年前にみられており,稀であるがブロム剤によるものと思われた.

Osamu Hashiguchi

Papers

Plasma abnormal prothrombin (Des-γ-carboxy prothrombin) as a marker of hepatocellular carcinoma

Clinical usefulness of serum cholylglycine determination in various liver diseases.

A case of lupoid hepatitis associated with hepatocellular carcinoma.

A successfully treated case with brain atrophy and fulminant hepatitis induced by overdosage of taking analgesics on the market.